PROJECT SUMMARY Learning disabilities and child obesity are major public health problems and understanding their root causes is a critical research priority. Inhibitory control has been cross-sectionally linked to obesity, although which disorder arises first is unclear. In addition, there is substantial overlap among fetal/infant environmental risk factors for both learning disabilities and for obesity. This may mean that inhibitory control is part of a shared causal pathway between environment and obesity. To our knowledge, no studies have addressed the upstream environmental causes that could explain the link between inhibitory control and obesity, nor have they addressed the temporal relationship between maladaptive behavior and obesity. A large body of research shows that environmental exposures during sensitive life periods affect key physiological processes and regulatory systems that orchestrate the development of multiple organ systems, including brain development and growth/obesity. The perinatal period is particularly important, as this is when cells and tissues differentiate most rapidly. The role of optimal oxidant balance for proper brain development, as well as its role in obesity is now increasingly recognized. Bringing all these concepts and observations together, we propose that prevalent, perinatal, paradigm pro-oxidant exposures ?air pollution, metals, and psychological stress- program child obesity by first causing maladaptive inhibitory control that ultimately leads to obesity. Furthermore, to better assess the role of oxidative stress (OS) we will measure mitochondrial DNA (mtDNA) damage in cord blood, as mtDNA is highly sensitive to OS and damage to its DNA propagates via mitosis. Damaged mtDNA biomarkers act as cumulative records of past oxidative stress, extending our work to include perinatal OS regardless of its cause. More broadly, our proposed biological framework means that one disease can be a causal risk factor for another, and that longitudinal pathways from environment to a disease should consider other disease states as possible intermediates. We believe this is a paradigm shifting concept that can unify several widely observed relationships. In addition, the path from environment to behavior to obesity may depend as much on exposure timing as on differences in exposure levels. We have therefore developed novel exposure methods that reconstruct perinatal environments in short time intervals. We combine these exposure tools with novel statistical approaches to allow us to objectively define susceptibility windows to air pollution and metals. Finally, we conduct this work in the ELEMENT cohort, a prospective pregnancy cohort study that has collected longitudinal exposure, covariate and phenotype data from pregnancy to age 7 years. In this proposal, we propose to assess inhibitory control and obesity phenotypes from 8-11, an age when child obesity rates rise dramatically, ensuring adequate power for our aims. Our approach will elucidate heretofore unexplained observations that multiple disorders (e.g., anthropometric, metabolic, neurobehavioral) arise from similar exposures and may have their roots in shared vulnerability to early environmental programming.